Cigarette smoking is the major environmental risk factor for the development of chronic obstructive pulmonary disease (COPD); however, the development of COPD is markedly variable among smokers. Genetic determinants of COPD other than severe alpha 1-antitrypsin deficiency are unproven. In the Boston Early-Onset COPD Study, genome scan linkage analysis with short tandem repeat markers has led to the identification of two regions of significant linkage and several other regions of suggestive linkage to COPD-related phenotypes. To identify the COPD genetic determinants within these chromosomal regions, we will perform fine mapping with association analysis of SNPs distributed throughout the linkage regions. We will enroll additional early-onset COPD pedigrees to replicate linkage regions from the previous genome scan and to increase the sample size for family-based association studies. Within two regions of linkage, SNPs will be systematically genotyped at 30 kb intervals in two pools of COPD cases (Boston Early-Onset COPD Study probands and National Emphysema Treatment Trial cases) and two pools of control subjects (Normative Aging Study and Nurses Health Study). For SNPs that demonstrate substantial allele frequency differences between the case and control pools, individual members of the pools will be genotyped to confirm the association between those SNPs and COPD. These confirmed SNP associations will be tested for replication using family-based association analysis in early-onset COPD pedigrees. For SNPs with replicated associations to COPD-related phenotypes, adjacent SNPs will be identified and genotyped in both family-based and case-control samples in order to identify key SNPs and haplotypes influencing the development of COPD. By emphasizing replication of both linkage and association results, the likelihood of robust and valid findings will be increased. If novel COPD susceptibility genes can be found following linkage and association analysis, new pharmacological interventions for COPD could be developed, improved understanding of COPD pathophysiology could result, and susceptible individuals could be identified.